Use of Botulinum Toxin in Spasmodic Dysphonia: A Review of Recent Studies

Spasmodic dysphonia (SD), also known as laryngeal dystonia, is a neurological voice disorder that causes involuntary spasms of the vocal cord muscles. This impacts speech to varying degrees and results in strained and strangled voice quality, as in adductor spasmodic dysphonia, or weak, quiet, and breathy, as in abductor spasmodic dysphonia. While there is currently no cure for SD, voice therapy and chemodenervation with botulinum toxin (btx) injections remain the mainstay of management. Surgery may be performed in some cases; however, btx injections are widely used to treat both adductor and abductor forms of SD. While btx injections may show vocal improvement in both types of SD, results can depend on several factors such as the general health of the patient, onset and severity of the condition, dosage, interval between injections, and expertise of the practitioner. While many studies have documented the efficacy of btx for improving vocal symptoms in individuals with SD, this review aims to discuss some of those studies from the last 10 years.

therapy, SD was also historically treated with psychotherapy, but both interventions have significantly limited improvement of the condition [6].
While surgical treatment has been in place much before chemodenervation became common, its long-term efficacy has not been well-established [5].
Chemodenervation with btx continues to remain the current standard of treatment for SD, but it is important to note that suitable dosage is determined individually after a titration period. This in many cases can take months to years before symptoms are relieved. In addition, factors such as body mass index (BMI), and general health issues such as lack of vitality, limitation in performing daily activities, physical and emotional health problems, and pain can show a positive correlation with higher effective doses and may be useful in guiding clinicians during the titration period, especially in the AdSD subset of patients [7]. In addition, almost one-third of patients presenting with AdSD present with an associated vocal tremor. These patients may not respond fully to treatment by injecting btx into the TA muscle group. This may be the result of the involvement of multiple muscle groups in the tremor. Hence, patients with a combination AdSD and vocal tremor and who do not respond to btx injection in the thyroarytenoid muscle alone may benefit from adding btx in the interarytenoid muscle for improved voice outcomes [8].
The use of btx is supported by a large number of studies that conclude its effectiveness, especially in the uncomplicated adductor form of SD [5]. However, the author aims to examine studies published in the last 10 years that have not only documented the efficacy of btx for the improvement of vocal symptoms in individuals with SD but also discussed new developments in its management.

Review Methodology
The author searched PubMed, PubMed Central (PMC), ResearchGate, and Google Scholar for relevant keywords such as vocal fold injection, laryngeal dystonia, vocal tremors, chemodenervation, spasmodic dysphonia, and botulinum toxin, as well as Medical Subject Headings (MeSH) "botulinum toxin" and "spasmodic dysphonia" to identify all relevant articles that discuss the role of btx injections in the management of voice symptoms in SD. The author included studies from 2012 to December 2022. The reference lists for all studies and other review articles were examined to identify additional studies.
Inclusion criteria included full-text, English-language articles from the last 10 years focusing mainly on the efficacy of btx injections in SD. Exclusion criteria included studies on complications of btx, studies not published in the English language, abstract-only articles, and those discussing non-btx interventions (unless btx was compared).

Results
A search on PubMed, PMC, ResearchGate, and Google Scholar yielded 149 studies. These included clinical trials, meta-analyses, randomized controlled trials, reviews, and systematic reviews. Studies not directly related to the topic were omitted to leave 39 articles. Of these, only 20 had full text available, from which the author selected 14 articles that were found to be relevant to this review.

Discussion
This article reviews studies published between 2012 and 2022, that have documented the efficacy of btx injections for the improvement of vocal symptoms in SD. The use of btx in the management of vocal symptoms in SD has remained the gold standard for over four decades. Studies that were reviewed also concluded the same, and new research also takes into consideration dose titration, techniques, and btx variants for optimum outcomes.
There have been attempts to explore surgical alternatives to btx for positive voice outcomes. For example, patients undergoing selective laryngeal adductor denervation-reinnervation in AdSD may show equal or superior outcomes to those of btx, as demonstrated through patient-oriented measures such as the Voice Handicap Index [9]. While the scope of this review is limited to btx injections, this study was included to compare it with available surgical alternatives.
A relatively low initial btx-A dose can be used with subsequent titration to achieve improved voice outcomes and fewer side effects such as breathiness [10]. While it was concluded that btx injections are efficient in the management of voice outcomes in SD with objective measurements, a study further concluded that the efficacy of recurring treatments remains stable over a period of time [11].
Factors such as age, gender, and smoking status do not appear to influence dosage stability [12]. Regarding dosage, btx injection for AdSD decreases consistently over subsequent injections after the initial two-dose titrations [13].
A study concluded that surgical procedures such as endoscopic laser thyroarytenoid myoneurectomy can potentially offer more stable and long-lasting voice quality compared to btx injections. However, in the study, 45% of patients showed deterioration after 12 months and needed a second procedure, which poses the question of whether it is comparatively a viable alternative to btx injections [14].
Gender, however, seems to have some influence in determining the dosage and desired outcomes. A study [15] concluded statistically and clinically that there is a significant correlation between female gender and higher average btx dose for symptom control, specifically in AdSD. Another study examined the association of SD with voice-related work productivity and concluded that gender may play a role in the desired outcomes. The study demonstrated that after one month of btx treatment, a greater number of women showed better outcomes compared to men. However, this gender-associated difference requires independent validation [16].
Btx injections as the treatment of choice in SD continue to be safe and efficacious [17], which another study demonstrated based on both objective and subjective assessments [18]. To reduce the side effects of btx, introducing hyaluronic acid has also been discussed in a study [19].
Recent studies also demonstrate that non-pharmacological factors such as education before the procedure, body position, pain, and stress sensation before btx may play a role in the effect of btx on AdSD patients [20]. In addition, a study compared unilateral and bilateral btx injections quantitatively and concluded that unilateral btx is useful for patients with an extended period with weak/breathy voice quality and those with dysphagia [21].
A study also demonstrated that incobotulinimtoxinA is equally useful as first-line treatment or in secondary non-responders to onabotulinumtoxinA [22].

Conclusions
The studies in this review have documented that btx injections continue to be the gold standard for the management of patients with SD. It is evident that globally, clinicians who have been exploring the best possible voice outcomes in patients with SD have confidence in the use of various variants of btx for different types of SD. This is mainly because btx injections not only provide a safe and reliable means of improving SD but are also easily available compared to other complex surgical interventions. While socioeconomic factors, patient counseling, gender, BMI, and other external factors may play some role, there is not enough evidence to conclude a strong correlation between dose variation in btx therapy and voice outcomes in SD. Therefore, more research is needed for a better understanding of these factors.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.